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  • Posted: 09/22/2011

Xenotropic Murine Leukemia Virus-related Virus (XMRV) Backgrounder

  1. What is XMRV?
    Xenotropic murine leukemia virus-related virus, or XMRV, is a retrovirus (of the gammaretrovirus genus) that was first isolated in 2006.

    Retroviruses are found in a wide range of cell types in both animals and humans. Most retroviruses are not known to be associated with any diseases and do not appear to damage the cells they infect. However, a few are associated with diseases in animals and humans and examples of disease-causing retroviruses in people are human immunodeficiency virus (HIV), which causes acquired immune deficiency syndrome (AIDS), and human T-cell leukemia virus (HTLV), which can cause leukemia and neurological problems.

  2. When was identification of XMRV initially reported?
    Scientists first reported identification of XMRV in 2006, in tissue samples from men with a particular subtype of prostate cancer. In 2009, other researchers reported finding XMRV in the white blood cells of some study participants diagnosed with chronic fatigue syndrome (CFS) as well as in healthy people. In all cases, however, not all laboratory samples tested positive for XMRV; furthermore, several subsequent studies in CFS patients failed to find links between XMRV and the disease. Some studies found viruses related to XMRV, known as polytropic murine leukemia viruses (P-MLV) in the blood of patients with CFS and healthy blood donors.

  3. Is XMRV a health risk?
    Researchers have not found evidence that XMRV causes any diseases in humans or in animals. The presence of an infectious agent, such as a virus, in diseased tissue does not mean that the agent causes the disease. In addition, although some early studies reported an association between XMRV and other MLV-related viruses, such as P-MLVs and human disease, the evidence was not definitive, and growing evidence has cast serious doubt about a link between XMRV/MLV-related viruses and CFS or prostate cancer.

    In December 2009, the U.S. Department of Health and Human Services assembled a team of scientists from the Office of the Assistant Secretary for Health, the Centers for Disease Control and Prevention, the Food and Drug Administration, the National Institutes of Health, and the Whittemore Peterson Institute, Reno, Nev. It was in the Whittemore Peterson Institute that researchers originally reported finding XMRV in the white blood cells of some patients with CFS. The team also included other researchers in the fields of transfusion medicine, blood banking, retrovirology, and chronic fatigue syndrome. This group, the Blood XMRV Scientific Research Working Group, has been identifying and designing research studies to evaluate whether XMRV poses a threat to the safety of the U.S. blood supply.

  4. What does the latest research show?
    In March 2011, scientists demonstrated that XMRV probably originated when xenografts, or cells transplanted from one species to another, were used to grow human prostate tumors in laboratory mice. These xenografts were used for studies to generate prostate cancer cell lines for further research. XMRV arose from the combination of two related mouse viruses and is nearly identical to the XMRV sequences thought to be found in most positive CFS studies. These results raise the possibility that the 2009 results linking XMRV to blood samples of CFS patients could be due to laboratory contamination or tests that may not have been able to detect XMRV at some levels of virus that might occur in the blood.

    In September 2011, a study in the journal Science failed to reproduce the presence of XMRV or P-MLVs in blood samples from patients with CFS who had previously tested positive for XMRV or P-MLVs, and from healthy donors (who served as a control group) who previously tested negative for these viruses. The study was blinded; i.e., the researchers did not know which blood samples were from healthy people versus from patients with CFS. The testing of the samples was performed by nine independent labs using highly sensitive and validated procedures, including those that looked for XMRV/P-MLV DNA or RNA, replication of the virus (whether it reproduced itself in cells), and the presence of antibodies. All blood samples were collected independently and processed by a centralized lab to ensure that each laboratory received identical sample sets that included replicated samples from each patient with CFS as well as control samples, some of which had XMRV inserted and some samples known to not have XMRV. None of the nine labs could reproducibly detect XMRV or MLV from 14 patients with CFS who had been found to have XMRV or P-MLV in tests conducted prior to 2011. These findings demonstrated that currently available XMRV/P-MLV tests cannot reproducibly detect virus markers or specific antibodies in blood samples. These new findings also supported multiple other studies raising concerns about the existence of blood-borne human infection with XMRV/P-MLV, and indicated that routine blood donor screening for XMRV/P-MLVs is not warranted at the current time.

    While these latest data do not support an association between XMRV/P-MLV infection and CFS, a study coordinated by W. Ian Lipkin, a professor of epidemiology at Columbia University’s Mailman School of Public Health, is examining this question in detail and will provide more data in the near future. This additional study involves testing fresh blood samples from 150 people living with CFS and 150 similar but healthy people. Through this effort, organizers will process, blind and send samples to laboratories at the FDA, the CDC and the Whittemore Peterson Institute for testing for the presence of XMRV, MLV, or related viruses. If one of the participating laboratories finds that a sample is positive for virus, further tests will be conducted to determine the validity of the result. If one participating lab finds a positive sample but another lab does not, the same samples can be shipped again, with a new blinded code, to be retested. It is hoped that the results from this study will be available by the end of 2011 or early 2012.

  5. Can XMRV be transmitted through blood transfusion?
    This possibility has been studied carefully. The Blood XMRV Scientific Research Working Group has coordinated review of specimens to assess XMRV test performance, and the prevalence and potential transmission of XMRV in the blood supply. The Sept. 22, 2011, Science paper appears to give strong support to the conclusion that the blood supply is secure.

  6. If researchers have a test for XMRV, why can’t it be used for diagnosis and screening of blood donors?
    At present, no transmission of XMRV has been identified, and there is no known evidence of XMRV infection or XMRV-related illness in transfusion recipients. Additionally, the Sept. 22, 2011 Science paper demonstrated that currently available XMRV/P-MLV assays cannot reproducibly detect virus markers or specific antibodies in blood samples and indicated that routine blood donor screening for XMRV/P-MLVs is not warranted at the current time.

  7. Should a person with diagnosed chronic fatigue syndrome donate blood?
    FDA regulations require that donors should be in good health at the time of donation. In June 2010, the AABB (formerly known as the Association of American Blood Banks) released an announcement recommending that member blood collectors provide educational materials to discourage people with CFS or myalgic encephalomyelitis from donating blood. This method has appeared to be effective in other settings; indeed, several nations have taken a similar approach.

    By December 2010, most U.S. blood banks had implemented the AABB’s recommendation, and the FDA’s scientific Blood Products Advisory Committee met to discuss how best to discourage people who have CFS from donating blood, considering the potential impact of donating on their health and the fact that CFS’s cause is unknown.

    While recent studies do not implicate XMRV, or related viruses, with chronic fatigue syndrome, AABB is continuing to advise that these patients refrain from donating blood. The recommendation is based on concern for the health of the potential blood donor. An AABB task force plans to re-evaluate this policy as it applies to potential donors who have been diagnosed with chronic fatigue syndrome but now feel well.

    For more information about AABB’s recommendation in response to the recent studies, visit http://www.aabb.org/pressroom/statements/Pages/statement092211.aspx.

  8. Should an individual who has been diagnosed, treated and currently in remission from prostate cancer donate blood? 
    There is no known association of prostate cancer with history of transfusion. In general, the FDA has not recommended deferral of donors who have a history of cancer due to lack of such an association.

  9. Should a person with diagnosed chronic fatigue syndrome or in remission from prostate cancer be an organ or tissue donor?
    At the present time, there are no recommendations to defer organ and tissue donations from individuals diagnosed with chronic fatigue syndrome.

 

Research activities at NIH

Several institutes that comprise the National Institutes of Health (NIH) have been working on approaches to rapidly answering questions about XMRV. The work that the institutes have done includes:

 

National Heart Lung and Blood Institute (NHLBI): The Blood XMRV Scientific Research Working Group

The Blood XMRV Scientific Research Working Group, which is led by the NHLBI, has been overseeing studies being performed by laboratory investigators at a range of federal and non-governmental laboratories. The researchers have conducted a methodical, rigorous study to examine assay performance and the prevalence and potential transmission of XMRV in the blood supply.

Phase I: Evaluate existing assays. The researchers compared existing methods in several laboratories to detect XMRV nucleic acids.

Using tissue culture cells and fluid infected with XMRV, scientists created and distributed coded panels that allowed for evaluating the analytical sensitivity (how well each test measures the presence of XMRV when it is actually present) of multiple XMRV nucleic acid tests. The XMRV nucleic acid test detection assays were found to be highly sensitive, and the overall similarity of results suggested that the analytical sensitivity of assays could not explain differences in XMRV detection in clinical samples reported by the participating laboratories.

Phase II: Optimize and standardize existing assays. In this phase, researchers performed a small clinical study to determine the best way to process blood specimens into samples for measuring XMRV. They compared whole blood with isolated blood cells as well as with plasma samples from four study participants previously found to be XMRV-positive by one laboratory. All the samples were processed shortly after collection or several days later. The results did not demonstrate any clear advantage to delaying the time at which samples are processed, and pointed to the need for evaluating more samples.

Phase III: Validate the assays using clinical samples. In this phase, researchers from nine laboratories performed tests to detect XMRV/P-MLVs in clinical samples from patients with CFS and negative and positive controls. The results of this study appeared Sept. 22, 2011, in Science.

The coded panels were comprised of clinical specimens that included samples from patients with CFS who were previously found to be positive for XMRV or P-MLVs, and samples from healthy controls whose blood previously tested negative for XMRV or P-MLVs, as well as samples with XMRV intentionally added. These samples were assembled into panels and distributed to nine participating laboratories. All blood samples were coded so individuals could not be identified, and special care was taken to prevent contamination. The panels were blinded, meaning that the researchers did not know the source or status of individual samples in the panels. These panels were used to define the clinical sensitivity and specificity of tests that detect XMRV/P-MLV nucleic acids and/or antibodies, as well as those that detect the intact virus itself (by culturing in cell lines). Specificity measures how well a test determines which samples that don’t have the viruses are correctly identified as not having the viruses. These panels allowed researchers to compare results from participating laboratories across the country and to better understand the laboratories’ performance in future studies. The study showed that currently available XMRV/P-MLV assays could not reproducibly detect virus markers or specific antibodies in blood samples, which supported other studies raising concerns about the existence of blood-borne human infection with XMRV/P-MLV. Overall, the results indicate that routine blood donor screening for XMRV/P-MLVs is not warranted at the current time.

 

National Institute of Allergies and Infectious Diseases (NIAID):

NIAID is supporting the previously described study by Ian Lipkin, M.D., of Columbia University’s Mailman School of Public Health. This study involves testing blood samples from 150 people living with CFS and 150 similar but healthy people. Through this effort, organizers will process, blind, and send samples to laboratories at the FDA, the CDC and the Whittemore Peterson Institute for testing for the presence of XMRV, MLV, or related viruses. If one of the participating laboratories finds that a sample tests positive for virus, further tests will be conducted to determine the validity of the result. If one participating laboratory finds a positive sample but another laboratory does not, the same samples can be shipped again, with a new blinded code, to be re-tested. It is hoped that the results from this study will be available by the end of 2011 or early 2012.

 

National Cancer Institute (NCI): 

The NCI has pursued three areas to develop XMRV assays, and efforts in two additional areas to provide researchers standards to develop their own assays:

NCI has developed a type of test, an enzyme-linked immunosorbent assay (ELISA), to detect antibodies in patients to several different antigens of XMRV. The presence of antibodies in individuals indicates exposure to the virus. The NCI ELISA for XMRV has been tested with samples from healthy donors and specialized cohorts, or groups.

Recent efforts to detect XMRV in human samples often use polymerase chain reaction (PCR is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA) on human genetic material. The sensitivity of these assays has varied. Standard clinical assays for HIV often determine viral RNA levels present in patient plasma. Given the ability of XMRV to replicate in human blood cells, NCI has developed a highly sensitive, PCR-based, DNA and RNA detection assay for virus in human plasma and cells. This assay can detect a single copy of the XMRV genome in one cubic centimeter of patient plasma.

The initial report in 2009 in Science of the association between XMRV and CFS indicated that the virus could be directly cultured from patient blood, using an assay that typically took several weeks. NCI developed a modified protocol that accelerates the detection of infectious XMRV to less than a week for samples with limiting amounts of virus. The assay can easily be performed by basic and clinical research laboratories in different settings throughout the world.

To aid the development of additional resources that can be used to examine XMRV prevalence, the NCI developed DNA molecules as vehicles to transfer foreign genetic material into another cell for the production of all XMRV proteins. These vectors were made available to all researchers free of cost, and enabled production of antibodies to study XMRV as well as critical XMRV enzymes as potential therapeutic targets. NCI also provided large quantities of purified XMRV. Purified virus was used as a standard in development of screening assays, as well as for basic studies on the properties of the virus.

The NCI timeline for development of reliable methodologies has been as follows:

July 2009                    Meeting of scientists to discuss public health impact of XMRV infection

October 2009             XMRV Planning Committee established

November 2009        -Construction of 40 recombinant clones expressing XMRV antigens
                                      -Development of assay to quantify XMRV DNA from tissues

December 2009        -6 XMRV proteins purified to homogeneity for diagnostic development
                                      -Development of assay to quantify XMRV RNA from plasma

January 2010            -Serological XMRV testing initiated using NCI-produced CA antigen
                                      -Sensitive XMRV indicator cell line established

February 2010           Evaluation of XMRV antigens for serological testing

March 2010                Large-scale production of XMRV virions as a source of antigen

April 2010                   64 XMRV expression clones delivered to AIDS Reagent Repository

September 2010       1st International Conference on XMRV (Bethesda, Md.)

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More Information:

As additional information on screening recommendations, research progress, and results become available, NIH will provide periodic updates on the NIH’s Trans-NIH ME/CFS Research Working Group Web site.

Other resources:

XMRV Research Studies to Date:

I. Research Articles

Identification of a novel Gammaretrovirus in prostate tumors of patients homozygous for R462Q RNASEL variant. Urisman A, Molinaro RJ, Fischer N, Plummer SJ, et al. PLoS Pathog. 2006 Mar;2:e25.

  • This study identified XMRV in prostate tumors of a subset of patients with R462Q genotype.

XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high grade tumors. Schlaberg R, Choe DJ, Brown KR, Thaker HM, et al. PNAS 2009;106:16351-6.

  • This study suggested an association of XMRV with prostate cancer.

Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, et al. Science 2009; 326:585-9.

  • This study identified XMRV in blood cells of 68 of 101 U.S. CFS patients and in 8 of 218 healthy controls.

Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors.  Lo S-C, Pripuzova N,  Li B,  Komaroff, AL,  et al. PNAS 2010; 107:15874-9.

  • The study demonstrated a strong association between a diagnosis of CFS and the presence of MLV-like virus gene sequences in blood. The study also showed that MLV-like viral gene sequences were detected in a small fraction of healthy blood donors. 

Prevalence of human gammaretrovirus XMRV in sporadic prostate cancer. Fischer N, Hellwinkel O, Schulz C, Chun FK, et al. J Clin Virol. 2008; 43:277-83.

  • This study found XMRV in 1 of 105 tissue samples from non-familial Northern European prostate cancer patients and in 1 of 70 control tissue samples.

Xenotropic murine leukemia virus-related gammaretrovirus in respiratory tract. Fischer N, Schulz C, Stieler K, Hohn O, et al. Emerg Infect Dis. 2010; 16:1000-2.

  • This study found XMRV in lung fluid of about 3 percent of 168 healthy controls and about 10 percent of 161 immunocompromised participants.

Detection of xenotropic murine leukemia virus-related virus in normal and tumor tissue of patients from the southern United States with prostate cancer is dependent on specific polymerase chain reaction conditions. Danielson BP, Ayala GE, Kimata JT. J Infect Dis. 2010;202:1470-7.

  • This study found XMRV in 32 of the 144 tissue specimens of patients with prostate cancer, independent of R462Q genotype.

No evidence of XMRV in Irish prostate cancer patients with R462Q mutation. D’Arcy F, Foley R, Perry A, Marignol L, et al. European Urology Supplements 2008; 7:271. (abstract not available online)

  • This study found no evidence of XMRV in prostate tissue of 139 Irish men with the genetic variant R462Q (RNase L mutation).

Lack of evidence for xenotropic murine leukemia virus-related virus(XMRV) in German prostate cancer patients. Hohn O, Krause H, Barbarotto P, Niederstadt L, et al. Retrovirology 2009;6:92.

  • This study of 589 tumor samples from German men with prostate cancer found no evidence of XMRV.

Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome. Groom HCT, Boucherit VC, Makinson K, Randal E, et al. Retrovirology 2010;7-10.

  • This study found no association between XMRV and CFS in 170 samples from U.K. CFS patients (from two cohorts) and 395 controls.

Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE. Erlwein O, Kaye S, McClure MO, Weber J, et al. 2010;5:e8519.

  • This study found no evidence of XMRV in 186 U.K. CFS patients.

Absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the United States. Switzer W, Jia H, Hohn O, Zheng H, et al. Retrovirology 2010;7:57.

  • This study found no evidence of XMRV in 50 U.S. CFS patients, 56 controls, or 41 blood donors.

Failure to detect XMRV in blood of individuals at high risk of blood-borne viral infections. Barnes E, Flanagan P, Brown A, Robinson N, et al. J Infectious Diseases 2010;202:1482-1485.

  • This study found no XMRV in blood samples of 230 patients with HIV or hepatitis C virus infection.

XMRV prevalence in patients with CFS or chronic immunomodulatory conditions.  Henrich TJ, Li JZ, Felsenstein D, Kotton CN, et al.  J infectious Diseases 2010;202:1478-1481.

  • This study found no XMRV in 43 patients with HIV infection, 32 patients with CFS, 26 transplantation patients and 95 patients presenting for medical care.

XMRV: A New Virus in Prostate Cancer? Aloia AL, Sfanos KS, Isaacs WB, Zheng Q, et al.

Cancer Res. 2010;70: 10028-33

  • This study found no XMRV in nearly U.S. 800 prostate cancer samples using a combination of real-time PCR and immunohistochemistry.

Absence of detectable xenotropic murine leukemia virus-related virus in plasma or peripheral blood mononuclear cells of human immunodeficiency virus Type 1-infected blood donors or individuals in Africa. Tang S, Zhao J, Viswanath R, Nyambi PN, et al.Transfusion. 2010;1537-2995

  •  This study found no XMRV in 199 plasma samples, 19 PBMNC samples, and 50 culture supernatants from PBMCs of blood donors from Cameroon found to be infected with HIV-1 and HIV-1 patients from Uganda.

Failure to detect Xenotropic murine leukaemia virus-related virus in Chinese patients with chronic fatigue syndrome. Hong P, Li J, Li Y. Virol J. 2010;7:224.

  • This study found no XMRV in Chinese populations including 65 CFS patients and 85 blood donor controls.

Recombinant Origin of the Retrovirus XMRV. Paprotka T, Delviks-Frankenberry K, Cingö O. et. al. Science Express (Internet) May 31, 2011;

  • This study reports laboratory contamination as the cause of the reported link in earlier papers of XMRV in CFS patients.

Failure to confirm Murine Leukemia-Related Viruses in the Blood of Patient with Chronic Fatigure Syndrome and healthy donors in a multi-laboratory blinded panel study. Simmons G, Glynn, SA, et al. Science Express.  Online Sept. 22, 2011. DOI: 10.1126/science.1213841

  • This study reports on the safety of the blood supply in regard to XMRV and MLV and the failure to find MLVs in re-tested samples.

 

II. Workshop Presentations/Abstracts

 

1st International Workshop on XMRV:  Pathogenesis, Clinical and Public Health Implications, Bethesda, MD. (September 2010): Workshop presentations

XMRV: examination of viral kinetics, tissue tropism, and serological markers of infection. Qui X, Swanson P, Luk K-C, Das Gupta J, et al. The 17th Conference on Retroviruses and Opportunistic Infections (2010).

  • This study in rhesus macaques provided preliminary data for disseminated XMRV infection and low but detectable virus in macaque blood.

XMRV Probably Originated through Recombination between 2 Endogenous Murine Retroviruses during in vivo Passage of a Human Prostate Cancer Xenograft.  Paprotka T, Delviks-Frankenberry K, Cingoz O, Martinez A, et al. The 18th Conference on Retroviruses and Opportunistic Infections (March 2011)

  • This study shows that XMRV was not present in the original CWR22 prostate tumor but was likely generated by subsequent genetic recombination during laboratory passaging of the tissue sample.

XMRV Induces a Nonproductive Infection in Human Lymphoid Tissue. Curriu M, Carrillo J, Massanella, Garcia E, et al. The 18th Conference on Retroviruses and Opportunistic Infections (March 2011)

  • This study shows that while XMRV can be integrated into human lymphoid tissue cells, the process did not result in a productive infection.

Single Copy and Single Genome Sequencing Assays to Detect XMRV in Human Blood Products. Kearney M, Wiegand A, Spindler J, Maldarelli F, et al. The 18th Conference on Retroviruses and Opportunistic Infections (March 2011)

  • This study reports a highly sensitive and specific (100 percent) nucleic acid testing method for distinguishing XMRV and closely related MLV in mouse cell DNA.